Yukihiko Shirayama

Showa University, Shinagawa, Tōkyō, Japan

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Publications (77)263.08 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Several lines of evidence suggest that glial cell-line derived neurotrophic factor (GDNF) plays an important role in the pathophysiology of neuropsychiatric and neurodegenerative disorders. In this study, we investigated the association between GDNF serum levels and the clinical status of medicated patients with schizophrenia. Sixty-three medicated patients with schizophrenia and 52 age- and sex-matched healthy controls were recruited. Patients were evaluated using the Brief Psychiatry Rating Scale, the Scale for the Assessment of Negative Symptoms (SANS) and neuropsychological tests. Serum levels of GDNF were determined using an ELISA method. Serum levels of GDNF did not differ between schizophrenia patients and controls. Higher GDNF serum levels were associated with better performances on the Digit Span in healthy controls but not in schizophrenics. At the same time, higher GDNF serum levels were associated with severe attention deficits on the SANS subscale, in schizophrenics. Our preliminary study suggests that serum levels of GDNF may be an unsuitable biomarker for schizophrenia, although it may be associated with working memory in healthy controls and the pathophysiology of attention deficits in schizophrenia.
    Neuroscience letters. 05/2014;
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    ABSTRACT: The psychological aspects of treatment-resistant and remitted depression are not well documented.
    PLoS ONE 01/2014; 9(10):e109137. · 3.53 Impact Factor
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    ABSTRACT: A meta-analysis study reported serum brain-derived neurotrophic factor (BDNF) levels as a potential biomarker for schizophrenia. However, at the time, commercially available human ELISA kits were unable to distinguish between pro-BDNF (precursor BDNF) and mature BDNF, because of limited antibody specificity. Here, we used new ELISA kits, to examine serum levels of mature BDNF and matrix metalloproteinase-9 (MMP-9), which converts pro-BDNF to mature BDNF in schizophrenia. Sixty-three patients with chronic schizophrenia and 52 age- and sex-matched healthy controls were enrolled. Patients were evaluated using the Brief Psychiatry Rating Scale, the Scale for the Assessment of Negative Symptoms (SANS) and neuropsychological tests. Neither serum mature BDNF nor MMP-9 levels differed between patients and controls. In male subgroups, serum MMP-9 levels of smoking patients were higher than those of non-smoking patients, but this was not observed in male controls or the female subgroup. In patients, serum mature BDNF levels were associated with SANS total scores and the Information subtest scores of the Wechsler Adult Intelligence Scale Revised (WAIS-R), while serum MMP-9 levels were associated with smoking and category fluency scores. These findings suggest that neither mature BDNF nor MMP-9 is a suitable biomarker for schizophrenia, although further studies using large samples are needed.
    Psychiatry research. 12/2013;
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    ABSTRACT: RATIONALE: Glutamatergic and γ-aminobutyric acid (GABA)ergic abnormalities have recently been proposed to contribute to depression. The learned helplessness (LH) paradigm produces a reliable animal model of depression that expresses a deficit in escape behavior (LH model); an alternative phenotype that does not exhibit LH is a model of resilience to depression (non-LH model). OBJECTIVES: We measured the contents of amino acids in the brain to investigate the mechanisms involved in the pathology of depression. METHODS: LH and non-LH models were subjected to inescapable electric footshocks at random intervals following a conditioned avoidance test to determine acquirement of predicted escape deficits. Tissue amino acid contents in eight brain regions were measured via high-performance liquid chromatography. RESULTS: The non-LH model showed increased GABA levels in the dentate gyrus and nucleus accumbens and increased glutamine levels in the dentate gyrus and the orbitofrontal cortex. The LH model had reduced glutamine levels in the medial prefrontal cortex. Changes in the ratios of GABA, glutamine, and glutamate were detected in the non-LH model, but not in the LH model. Reductions in threonine levels occurred in the medial prefrontal cortex in both models, whereas elevated alanine levels were detected in the medial prefrontal cortex in non-LH animals. CONCLUSIONS: The present study demonstrates region-specific compensatory elevations in GABA levels in the dentate gyrus and nucleus accumbens of non-LH animals, supporting the implication of the GABAergic system in the recovery of depression.
    Psychopharmacology 04/2013; · 4.06 Impact Factor
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    ABSTRACT: Recently, we reported that low reward dependence, and to a lesser extent, low cooperativeness in the Temperature and Character Inventory (TCI) may be risk factors for treatment-resistant depression. Here, we analyzed additional psychological traits in these patients. We administered Costa and McCrae's five-factor model personality inventory, NEO Personality Inventory-Revised (NEO-PI-R), to antidepressant-treatment resistant depressed patients (n = 35), remitted depressed patients (n = 27), and healthy controls (n = 66). We also evaluated the relationships between scores on NEO and TCI, using the same cohort of patients with treatment-resistant depression, as our previous study. Patients with treatment-resistant depression showed high scores for neuroticism, low scores for extraversion, openness and conscientiousness, without changes in agreeableness, on the NEO. However, patients in remitted depression showed no significant scores on NEO. Patients with treatment-resistant depression and low openness on NEO showed positive relationships with reward dependence and cooperativeness on the TCI. Many studies have reported that depressed patients show high neuroticism, low extraversion and low conscientiousness on the NEO. Our study highlights low openness on the NEO, as a risk mediator in treatment-resistant depression. This newly identified trait should be included as a risk factor in treatment-resistant depression.
    PLoS ONE 01/2013; 8(9):e71964. · 3.53 Impact Factor
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    ABSTRACT: The clinical outcome of antidepressant treatment in patients with major depressive disorder (MDD) is thought to be associated with personality traits. A number of studies suggest that depressed patients show high harm avoidance, low self-directedness and cooperativeness, as measured on the Temperament and Character Inventory (TCI). However, the psychology of these patients is not well documented. Psychological evaluation using Cloninger's TCI, was performed on treatment-resistant MDD patients (n = 35), remission MDD patients (n = 31), and age- and gender-matched healthy controls (n = 174). Treatment-resistant patients demonstrated high scores for harm avoidance, and low scores for reward dependence, self-directedness, and cooperativeness using the TCI, compared with healthy controls and remission patients. Interestingly, patients in remission continued to show significantly high scores for harm avoidance, but not other traits in the TCI compared with controls. Moreover, there was a significant negative correlation between reward dependence and harm avoidance in the treatment-resistant depression cohort, which was absent in the control and remitted depression groups. This study suggests that low reward dependence and to a lesser extent, low cooperativeness in the TCI may be risk factors for treatment-resistant depression.
    PLoS ONE 01/2013; 8(5):e63756. · 3.53 Impact Factor
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    ABSTRACT: Cognitive impairments in schizophrenia are associated with suboptimal psychosocial performance. Several lines of evidence have suggested that endoplasmic reticulum protein sigma-1 receptors were involved in cognitive impairments in patients with schizophrenia and that the sigma-1 receptor agonist fluvoxamine was effective in treating cognitive impairments in animal models of schizophrenia and in some patients with schizophrenia. A randomized, double-blind, placebo-controlled, parallel trial of fluvoxamine adjunctive therapy in patients with schizophrenia was performed. A total of 48 patients with chronic schizophrenia were enrolled. Subjects were randomly assigned to an 8-week administration of add-on fluvoxamine (n = 24, titrated up to 150 mg/d) or placebo (n =24) in a total 12-week double-blind trial. The primary outcome measure was the Cambridge Neuropsychological Test Automated Battery (CANTAB), assessing visual memory, working memory, attention, and executive function. The secondary outcome measures were the Positive and Negative Syndrome Scale, the Scale for the Assessment of Negative Symptoms, the Quality of Life Scale, and the Montgomery-Åsberg Depression Rating Scale. Fluvoxamine was well tolerated. No significant time × group interaction effects were observed in the scores of the CANTAB, Positive and Negative Syndrome Scale, Scale for the Assessment of Negative Symptoms, Quality of Life Scale, or the Montgomery-Åsberg Depression Rating Scale. However, in secondary analyses, the change from baseline to end point on the Spatial Working Memory strategy score (executive function) of CANTAB improved in the fluvoxamine group. This study suggests no major benefit of fluvoxamine adjunctive therapy to improve cognitive impairments in patients with schizophrenia. Nevertheless, a further study using a large sample size will be needed to confirm the secondary analyses findings.
    Journal of clinical psychopharmacology 08/2012; 32(5):593-601. · 5.09 Impact Factor
  • Masatoshi Suzuki, Koichi Sato, Yukihiko Shirayama
    Nippon rinsho. Japanese journal of clinical medicine 12/2011; 69 Suppl 10(Pt 2):47-51.
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    ABSTRACT: A 68-year-old woman showed obsessive thought that she could not remember the names of people or items that she saw. She repeatedly asked her husband to recall names of unspecified people and checked the garbage to find the names of items. The patient had a history of cerebral infarctions in the left middle cerebral artery regions 2 and 15 months before the emergence of her symptoms. A magnetic resonance imaging examination showed signs of an old infarction in the left basal ganglia and ischemic signs in the right temporal lobe. Her obsessive-compulsive symptoms relating to words were successfully treated with a serotonin selective reuptake inhibitor, paroxetine, at the dose of 40 mg/d. Her scores on the Yale-Brown Obsessive Compulsive Scale reduced from 31 to 8 points after this treatment. This case may suggest therapeutic modulation of language-related cortical activity elicited by paroxetine.
    Clinical neuropharmacology 11/2011; 34(6):260-1. · 2.35 Impact Factor
  • Yukihiko Shirayama, Takeshi Konishi, Kenji Hashimoto
    Journal of clinical psychopharmacology 10/2011; 31(5):659-61. · 5.09 Impact Factor
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    ABSTRACT: Patients with depression showed a decrease in plasma and cerebrospinal fluid allopregnanolone (ALLO). But antidepressants increased the contents of ALLO in the rat brain. We examined the antidepressant-like effects of infusion of ALLO into the cerebral ventricle, hippocampus, amygdala, nucleus accumbens, or prefrontal cortex of learned helplessness (LH) rats (an animal model of depression). Of these regions, infusions of ALLO into the cerebral ventricle, the CA3 region of hippocampus, or the central region of amygdala exerted antidepressant-like effects. Infusion of ALLO into the hippocampal CA3 region or the central amygdala did not produce memory deficits or locomotor activation in the passive avoidance and open field tests. It is well documented that ALLO exerts its effects through GABA receptors. Therefore, we examined the antagonistic effects of flumazenil (a GABA receptor antagonist) on the antidepressant-like effects of ALLO. Coinfusion of flumazenil with ALLO into the hippocampal CA3 region, but not into the central amygdala, blocked the antidepressant-like effects of ALLO. However, coinfusion of (+)MK801 (an NMDA receptor antagonist), but not cycloheximide (a protein synthesis inhibitor), blocked the antidepressant-like effects of ALLO in the central amygdala. These results suggest that ALLO exerts antidepressant-like effects in the CA3 region of hippocampus through the GABA system and in the central region of amygdala, dependently on the activation of the glutamatergic mechanisms.
    Hippocampus 10/2011; 21(10):1105-13. · 5.49 Impact Factor
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    ABSTRACT: Previous studies have indicated that minocycline might function as an antidepressant drug. The aim of this study was to evaluate the antidepressant-like effects of minocycline, which is known to suppress activated microglia, using learned helplessness (LH) rats (an animal model of depression). Infusion of minocycline into the cerebral ventricle of LH rats induced antidepressant-like effects. However, infusion of minocycline into the cerebral ventricle of naïve rats did not produce locomotor activation in the open field tests, suggesting that the antidepressant-like effects of minocycline were not attributed to the enhanced locomotion. LH rats showed significantly higher serotonin turnover in the orbitofrontal cortex and lower levels of brain-derived neurotrophic factor (BDNF) in the hippocampus than control rats. However, these alterations in serotonin turnover and BDNF expression remained unchanged after treatment with minocycline. On the contrary, minocycline treatment of LH rats induced significant increases in the levels of dopamine and its metabolites in the amygdala when compared with untreated LH rats. Taken together, minocycline may be a therapeutic drug for the treatment of depression.
    Pharmacology Biochemistry and Behavior 09/2011; 100(3):601-6. · 2.82 Impact Factor
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    ABSTRACT: Brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of schizophrenia. The aim of this study was to examine the associations of serum BDNF levels with the cognition and clinical characteristics in patients with schizophrenia. Sixty-three patients with schizophrenia and 52 age- and sex-matched healthy controls were examined with neuropsychological tests. Serum BDNF levels were determined by enzyme-linked immunosorbent assay (ELISA). There were no significant differences in serum BDNF levels between normal controls and patients with schizophrenia. Serum BDNF levels of normal controls showed negative correlations with verbal working memory, but this was not the case with schizophrenic patients. Meanwhile, serum BDNF levels of schizophrenic patients showed positive correlations with the scores of the Scale for the Assessment of Negative Symptoms (SANS) and the Information subtest scores of Wechsler Adult Intelligence Scale Revised (WAIS-R). Serum BDNF levels are related with the impairment of verbal working memory and negative symptoms in patients with schizophrenia.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 09/2011; 35(8):1836-40. · 3.55 Impact Factor
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    ABSTRACT: The astrocyte is a major component of the neural network and plays a role in brain function. Previous studies demonstrated changes in the number of astrocytes in depression. In this study, we examined alterations in the number of astrocytes in the learned helplessness (LH) rat, an animal model of depression. The numbers of activated and nonactivated astrocytes in the dentate gyrus (molecular layer, subgranular zone, and hilus), and CA1 and CA3 regions of the hippocampus were significantly increased 2 and 8 days after attainment of LH. Subchronic treatment with imipramine showed a tendency (although not statistically significant) to decrease the LH-induced increment of activated astrocytes in the CA3 region and dentate gyrus. Furthermore, subchronic treatment of naïve rats with imipramine did not alter the numbers of activated and nonactivated astrocytes. However, the antidepressant-like effects of imipramine in the LH paradigm were blocked when fluorocitrate (a reversible inhibitor of astrocyte function) was injected into the dentate gyrus or CA3 region. Injection of fluorocitrate into naive rats failed to induce behavioral deficits in the conditioned avoidance test. These results indicate that astrocytes are responsive to the antidepressant-like effect of imipramine in the dentate gyrus and CA3 region of the hippocampus.
    Hippocampus 08/2011; 21(8):877-84. · 5.49 Impact Factor
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    ABSTRACT: Benzodiazepines carry the risk of inducing cognitive impairments, which may go unnoticed while profoundly disturbing social activity. Furthermore, these impairments are partly associated with the elimination half-life (EH) of the substance from the body. The object of the present study was to examine the effects of etizolam and ethyl loflazepate, with EHs of 6 h and 122 h, respectively, on information processing in healthy subjects. Healthy people were administered etizolam and ethyl loflazepate acutely and subchronically (14 days). The auditory P300 event-related potential and the neuropsychological batteries described below were employed to assess the effects of drugs on cognition. The P300 event-related potential was recorded before and after drug treatments. The digit symbol test, trail making test, digit span test and verbal paired associates test were administered to examine mental slowing and memory functioning. Acute administration of drugs caused prolongation in P300 latency and reduction in P300 amplitude. Etizolam caused a statistically significant prolongation in P300 latency compared to ethyl loflazepate. Furthermore, subchronic administration of etizolam, but not ethyl loflazepate, still caused a weak prolongation in P300 latency. In contrast, neuropsychological tests showed no difference. The results indicate that acute administration of ethyl loflazepate induces less effect on P300 latency than etizolam.
    Annals of General Psychiatry 11/2010; 9:37. · 1.57 Impact Factor
  • Progress in Neuro-Psychopharmacology and Biological Psychiatry 10/2010; 34(7):1345-6. · 3.55 Impact Factor
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    ABSTRACT: l-Serine is required for the synthesis of glycine and d-serine, both of which are NMDA receptor co-agonists. Although roles for d-serine and glycine have been suggested in schizophrenia, little is known about the role of the l-serine synthesizing cascade in schizophrenia or related psychiatric conditions. Here we report a patient with schizophrenia carrying a balanced chromosomal translocation with the breakpoints localized to 3q13.12 and 9q21.2. We examined this proband and her son with schizotypal personality disorder for chromosomal abnormalities, molecular expression profiles, and serum amino acids. Marked decrease of l-serine and glutamate was observed in the sera of the patient and her son, compared with those in normal controls. Interestingly, expression of PSAT1 gene, which is located next to the breakpoint and encodes one of the enzymes in the l-serine synthesizing cascade, was reduced in both patient and her son. Direct effect of impaired PSAT1 gene expression on decreased serum l-serine level was strongly implicated by rat astrocyte experiments. In summary, we propose an idea that PSAT1 may be implicated in altered serine metabolism and schizophrenia spectrum conditions.
    Neuroscience Research 10/2010; 69(2):154-60. · 2.20 Impact Factor
  • Pharmacopsychiatry 06/2010; 43(4):151-2. · 2.11 Impact Factor
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    ABSTRACT: Cognitive deficits in schizophrenia are associated with psychosocial deficits that are primarily responsible for the poor long-term outcome of this disease. Auditory sensory gating P50 deficits are correlated with neuropsychological deficits in attention, one of the principal cognitive disturbances in schizophrenia. Our studies suggest that the alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) agonist tropisetron might be a potential therapeutic drug for cognitive deficits in schizophrenia. Therefore, it is of particular interest to investigate the effects of tropisetron on the cognitive deficits in patients with schizophrenia. A randomised, placebo-controlled trial of tropisetron in patients with schizophrenia was performed. A total of 40 patients with chronic schizophrenia who had taken risperidone (2 to 6 mg/day) were enrolled. Subjects were randomly assigned to a fixed titration of tropisetron (n = 20, 10 mg/day) or placebo (n = 20) in an 8-week double-blind trial. Auditory sensory gating P50 deficits and Quality of Life Scale (QLS), Cambridge Neuropsychological Test Automated Battery (CANTAB), and Positive and Negative Syndrome Scale (PANSS) scores were measured. In all, 33 patients completed the trial. Tropisetron was well tolerated. Administration of tropisetron, but not placebo, significantly improved auditory sensory gating P50 deficits in non-smoking patients with schizophrenia. The score on the rapid visual information processing (sustained visual attention) task of CANTAB was significantly improved by tropisetron treatment. Total and subscale scores of PANSS were not changed by this trial. QLS scores in the all patients, but not non-smoking patients, were significantly improved by tropisetron trial. This first randomised, double-blind, placebo-controlled trial supports the safety and efficacy of adjunctive tropisetron for treatment of cognitive deficits in schizophrenia.
    Annals of General Psychiatry 01/2010; 9:27. · 1.57 Impact Factor
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    ABSTRACT: We measured brain metabolites in the medial prefrontal cortex of 19 schizophrenic patients and 18 healthy controls by 3 T proton magnetic resonance spectroscopy ((1)H MRS), and examined the relationship between prefrontal cortex-related neurocognitive functions and brain metabolites in the medial prefrontal cortex. The patients with schizophrenia exhibited deficits on the verbal fluency, Wisconsin card sorting test (WCST), trail making test, Stroop test and digit span distraction test (DSDT), but not on the Iowa gambling test. The patients showed statistical significant changes in the ratio of glutamine/glutamate, the ratio of N-acetyl-l-aspartate (NAA)/glycerophosphorylcholine plus phosphorylcholine (GPC+PC) and the levels of taurine in the medial prefrontal cortex compared with normal controls. Furthermore, we found significant correlations of the ratio of glutamine/glutamate with WCST and DSDT scores, the ratio of NAA/(GPC+PC) with verbal fluency and WCST scores, and the levels of taurine with scores on the Stroop test and Trail making test A among the participants. The ratios of NAA/(GPC+PC) and (GPC+PC)/(Cr+PCr) had significant relationships with the duration of untreated psychosis of the schizophrenic patients. The glutamine/glutamate ratio and levels of taurine were significantly related to the duration of illness of the patients. These data suggest that specific metabolites of the medial prefrontal cortex are associated with the neurocognitive deficits in schizophrenia.
    NeuroImage 10/2009; 49(3):2783-90. · 6.25 Impact Factor

Publication Stats

2k Citations
263.08 Total Impact Points

Institutions

  • 1999–2013
    • Showa University
      • Department of Psychiatry
      Shinagawa, Tōkyō, Japan
  • 2008–2012
    • Chiba University
      • Department of Psychiatry
      Chiba-shi, Chiba-ken, Japan
  • 2004–2007
    • Tottori University
      • • Faculty of Medicine
      • • Department of Multidisciplinary Internal Medicine
      Tottori, Tottori-ken, Japan
    • Hamamatsu University School of Medicine
      • Research Center for Child Mental Development
      Hamamatu, Shizuoka, Japan
  • 1993–2004
    • National Center of Neurology and Psychiatry
      • • Department of Psychophysiology
      • • Department of Mental Disorder Research
      Кодаиры, Tōkyō, Japan
    • Panic Disorder Research Center - Nagoya Mental Clinic
      Nagoya, Aichi, Japan
  • 2002
    • Yale University
      • Department of Psychiatry
      New Haven, Connecticut, United States
  • 1998
    • National Institute of Mental Health and Neuro Sciences
      Bengalūru, Karnātaka, India